The objective of this program of research is to study in detail the mechanism by which different classes of compounds inhibit the DNA polymerase activity of the reverse transcriptase present in RNA tumor viruses. This is in partial fulfillment of a long term program, based on the use of specific or selective inhibitors, to study polymerases engaged in the process of transformation. Two types of inhibitors will be studied, each with a different mode of action: rifamycin SV derivatives, which act by binding directly to the enzyme; tilorone derivatives, which inhibit by binding to templates. Particular emphasis will be given in this proposal to the study of rifamycin derivatives, a study which we have already systematically initiated. Selected inhibitors will be examined with respect to: the site of inhibition; the reversibility of inhibition; step(s) of transcription at which the drug acts; effects on the formation and dissociation of the complex between the enzyme and different templates; effect on the apparent Km for template, primer, triphosphates; influence of the chemical structure of the side chain component on the Hill number; structural requirements of the drug for inhibition; differential inhibition of the RNase H and polymerase activities of the viral reverse transcriptase; and the comparative effect on mammalian DNA and RNA polymerases. The study of the mechanism of action of inhibitors will be useful for understanding the mechanism of transcription by the reverse transcriptase, and in turn, will provide information for designing more specific inhibitors. Considering the possible viral etiology of human cancer, specific inhibitors of the reverse transcriptase (or of other polymerases involved in the transcription of viral specific information) may be useful for elucidating any role of such enzymes in neoplasia.